EVIDENCE FOR HETERODIMERIZATION AND FUNCTIONAL INTERACTION OF THE UROTENSIN II AND THE ANGIOTENSIN II TYPE 1 RECEPTORS
Bibliographic record
Abstract
BACKGROUND AND PURPOSE Despite the observation of synergistic interactions between the urotensinergic and angiotensinergic systems, the interplay between the urotensin II receptor (hUT) and the angiotensin II type 1 receptor (hAT1R) in regulating cellular signaling under physiological and pathophysiological conditions remains incompletely understood. Notably, the interaction between hUT and hAT1R could engender reciprocal allosteric modulations of their signaling signatures, defining a unique role for these complexes in cardiovascular physiology and pathophysiology. EXPERIMENTAL APPROACH The physical interaction between hUT and hAT1R receptors was evaluated by co-immunoprecipitation, bioluminescence resonance energy transfer (BRET) and FlAsH BRET-based conformational biosensors. To analyze how this functional interaction regulated proximal and distal hUT-associated signaling pathways, we used BRET-based signaling biosensors and western blots to profile pathway-specific signaling in HEK 293 cells expressing hUT, hAT1R or both. KEY RESULTS We observed that hUT-hAT1R heterodimers triggered distinct signalling outcomes, in particular Gq/ G13/Gi/DAG/-arrestin-1/ERK1/2, compared to their respective parent receptors alone. Notably, co-transfection of hUT and hAT1R slightly potentiated hUII-induced Gq activation but significantly reduced the potency and efficacy of Ang II to mediate Gq activation. Using a FlAsH-walk approach, we observed that the presence of unliganded hUT altered conformational dynamics of hAT1R but that addition of hUII or URP did not produce further modulations. CONCLUSION Assembly of hUT with hAT1R might be important for allosteric modulation of outcomes associated with specific hardwired signaling complexes in healthy and disease states. Our work validates such complexes as potential targets to promote the design of compounds that modulate heterodimer function selectively.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".